14Beta,18-(epoxyethanoimino) steroids

ABSTRACT

Compounds of the class of 14 Beta ,18-(epoxyethanoimino)pregnane derivatives and their pharmceutically acceptable acid addition salts have cardiotonic activity and are active ingredients of pharmaceutical compositions; a typical embodiment is 1&#39;&#39;-methyl-2&#39;&#39;-oxo.3 Beta ,20 xi -diacetoxy-14 Beta ,18(epoxyethanoimino)-5 Alpha ,17 Alpha -pregane.

United States Patent Wehrli et al.

3,869,452 Mar. 4, 1975 l4BETA,l8-( EPOXYETHANOIMINO) STEROIDS Inventors:Hansuli Wehrli, Schaffhausen;

Oskar .leger, Zollikerberg/Zurich, both of Switzerland Assignee:Ciba-Geigy Corporation, Ardsley,

Filed: Oct. 19, 1972 Appl. No.: 298,913

Related US. Application Data Continuation of Ser. No. 82,l83, Oct. 19,1970, abandoned.

Foreign Application Priority Data Oct. 24, 1969 Switzerland 15902/69July 24. I970 Switzerland 11242/70 US. Cl ..260/239.55 R, 260/23955 C,260/3974, 26()/397.45, 260/397.5, 260/999 Int. Cl. C07c 173/10 PrimaryE.\'aminer-Henry A. French Attorney, Agent, or Firm-Joseph G. Kolodny;Ronald A. Daignault; John J. Maitner [57} ABSTRACT Compounds of theclass of 14B,l8-(epoxyethanoimino)-pregnane derivatives and theirpharmceutically acceptable acid addition salts have cardiotonic activityand are active ingredients of pharmaceutical compositions; a typicalembodiment is l'-methyl-2-ox0.3B,2()-diacetoxy-14,13,18-(ep0xyethanoimin0)-5a,l7a-pregane,

14 Claims, N0 Drawings 1 14BETA,1S-(EPOXYETHANOIMINO) STEROIDS This is acontinuation of application Ser. No. 82,183, filed October l9, 1970 nowabandoned.

The present invention relates to derivatives of l4,B,l-8-(epoxyethanoimino)-pregnanes and pharmaceutically acceptable acidaddition salts thereof with useful pharmacological activity and topharmaceutical compositions containing them.

More particularly, the present invention relates to compounds of theformula I wherein:

R represents a lower alkyl group, the benzyl group or hydrogen,

R represents an oxo radical or two hydrogen atoms,

R represents a free or protected oxo radical, or a free, esterified oretherified hydroxyl group and a hydrogen atom,

R represents a free or protected oxo radical, or a free, esterified oretherified hydroxyl group and a hydrogen atom, or a free or etherifiedhydroxyl group and together with R, an epoxy radical,

R and R each independently represent a free or protected oxo radical, ora free, esterified or etherified hydroxyl group and a hydrogen atom, ortwo hydrogen atoms, or, when occurring at a double bond, one hydrogenatom.

R represents an a or ,B-oricnted hydrogen atom,

R represents an a-oriented hydrogen atom, an a-oriented hydroxyl group,or together with R, an epoxy radical, and

R represents an aor B-oriented hydrogen atom, or

a free, esterified or etherified hydroxyl group,

whereby double bonds may be present in the positions 5 or 4, when Rrepresents a free oxo radical, as well as 7, 9 (I1) and 16 correspondingto the dotted lines with the elimination of R R and/or R9,

as well as to pharmaceutically acceptable acid addition salts of thecompounds of formula I in which R designates two hydrogen atoms.

As lower alkyl group, R is, e.g. a methyl group, an ethyl group, ann-propyl group, an isopropyl group, a butyl group or pentyl group. Theafore-mentioned esterified hydroxyl groups in 20-position are derivedfrom lower alkanoic acids such as: acetic acid, propionic acid, butyricacid, isobutyric acid, valeric acid,

isovaleric acid, pivalic acid or formic acid; or from pyrrole carboxylicacids and alkyl-substituted pyrrole carboxylic acids such as2,4,5-trimethylpyrrole-3- carboxylic acid,2,4-dimethylpyrrole-3-carboxylic acid or2-ethyl-4-methylpyrrole-3-carboxylic acid. Esterified hydroxyl groups inthe positions 3, 7 and/or l l are derived from lower alkanoic acids,e.g. from the aforementioned lower alkanoic acids.

Suitable etherified hydroxyl groups in the 3-, 20-, 7-, l 1- and/orl7-positions are, in particular, those which are derived from loweralkanols such as methyl alcohol, ethyl alcohol, propyl alcohol,isopropyl alcohol, or from the butyl or amyl alcohols. Suitable asetherified hydroxyl group are, for example, also the(tetrahydro-ZH-pyran-Z-yl)-oxy group, the4-methoxytetrahydropyran-4-yloxy group and thel,l-methoxycyclohexyl-l-yloxy group, as well as the benzyloxy group andthe triphenyl-methoxy group. Protected oxo radicals in the 3-, 20,7--and/or ll-positions are ketal groupings which are derived from loweralkane-diols or from lower alkanols.

The compounds of the general formula I possess valuable pharmacologicalproperties. They selectively raise the permeability of muscle and nervemembranes for sodium ions. The resulting increase of influx of sodiumions causes an acceleration of depolarization and thus also of musclecontraction. Since according to re cent evidence cardio-activesubstances of the digitalisstrophanthin type hinder the transfer ofactive sodium ions out of the muscle fibers by blocking thetransferadenosin triphosphate ase of the membranes thus likewiseincreasing the sodium concentration, and accelerating depolarization andmuscle contraction, the

compounds of general Formula ll lead ultimately, via the differentmechanism already mentioned, to therapeutic effects which are similar tothose of the cardio active digitalis substances, such as strengtheningof the systole and of the minute volume of the heart.

In addition, the compounds of general Formula I in which R representsthe oxo radical are new intermediate products for the production of thepharmacologically more important compounds of general Formula I having 2hydrogen atoms as R However, also the lat ter compounds of generalFormula I, in particular those having a free hydroxyl group in20-position, can be used as intermediate products for the production ofother pharmacologically valuable substances. Of particular importancenew pharmacologically active substances and as intermediate productstherefor are the compounds of the general Formula Ia 3 wherein:

R represents a lower alkyl group or the benzyl group.

and R R R R R R and R have the meaning given for Formula 1, wherebydouble bonds may be present in the positions 5, 7 and 16 correspondingto the dotted lines, with the elimination of R and R accordingly. Thecompounds of general Formula la in which R represents the x0 radical areparticularly important as intermediate products for the compounds ofgeneral Formula la having two hydrogen atoms as R The latter compoundscan also be used as intermediate products; e.g. they can be convertedinto the corresponding semiketals, i.e. compounds having a free3B-hydroxy group. These and other modifications of the compounds ofgeneral Formulas I and la are described more in detail further below.

The process for the production the compounds of general Formula I of thepresent application is characterized in that a compound of the generalFormula II wherein:

X represents a halogen atom such a chlorine, bromine or iodine, and R RR R R R R and R have the meaning given for Formula I, and the doublebonds mentioned there can be present, is cyclized in thepresence of anacid-binding agent in a solvent which is inert and/or one containing ahydroxyl group; if desired, the lactam grouping is then reduced by meansof a complex hydride to a cyclic amino group; and/or esterified hydroxylgroups in R R R and/or R protected oxo radicals, or an etherifiedhydroxyl group occurring together with an epoxy radical in R are setfree; and/or free oxo radicals R R R and R are reduced; and/or freehydroxyl groups in R R R and R are oxidized to oxo radicals, oresterified, or etherified; and/or, if desired, compounds of generalFormula I in which R denotes two hydrogen atoms, are converted into acidaddition salts with inorganic or organic acids. For the cyclizationaccording to the process of the compounds of the above general Formulall, metal hydroxides are preferably used as acid-binding agents,

such as: silver hydroxide, sodium or potassium hydroxide solution, basicmetal salts such as sodium and potassium carbonate, or sodium andpotassium bicarbonate, alkali metal alcoholates such as, e.g. sodiummethylate, sodium ethylate or potassium-tert.butylate, metal hydridessuch as sodium hydride, calcium hydride or lithium aluminium hydride.The solvents used for the reaction according to the process are,preferably, aliphatic, cyclic or aromatic hydrocarbons, especiallybenzene or toluene, ethers such as, e.g. diethyl ether, tetrahydrofuran,dioxane, or also dimethylsulphoxide, dimethylformamide and/or alcoholssuch as, e.g. methanol, ethanol or tert. butanol. An advantageousembodiment of i the cyclization is the reaction of the startingmaterials with sodium hydride in a mixture, preferably l:l, of benzeneand tetrahydrofuran in the presence of catalytic amounts of an alcohol,especially methanol or ethanol.

The lactams obtained after cyclization and which are embraced by thegeneral Formula I, in which lactams R is an oxo radical, can beconverted according to the process by reduction into the correspondingcyclic amines in which R denotes two hydrogen atoms, and- /or modifiedat the ZO-oxygen group, and, when pres ent, at the oxygen groups in thepositions 3, 7 and/or 1 l, in a known manner. Thus, for example a lactamembraced by the general Formula I may be converted by treatment with acomplex hydride, such as lithium aluminium hydride, in an ether such asdiethyl ether, tetrahydrofuran or dioxane, into the corresponding cyclicamine.

By the reduction with lithium aluminium hydride, the esterified hydroxylgroups are also set free. When the lactams are not reduced in thismanner, the hydroxyl groups can be set free, e.g., by alkalinehydrolysis. Oxo radicals protected by ketal groupings can be set free bytreatment with acids under mild conditions, e.g. with mixtures ofaqueous perchloric acid and glacial acetic acid at room temperature.Under the same conditions, an alkoxy group in 3fi-position together witha 3a,9a-epoxy radical is converted into the hydroxyl group. Free oxoradicals can be reduced to hydroxyl groups, e.g., by means of complexhydrides such as sodium boro-hydride or tri-tert-butoxy-lithiumaluminium hydride, e.g. in tetrahydrofuran. Free hydroxyl groups can beoxidized to oxo groups, either before or following reduction of thelactam group, by means of the Oppenauer reaction or with the aid ofcompounds of 6-valent chromium, e.g. chromium trioxide in pyridine.

Hydroxyl groups can be esterified in a known manner, e.g. by treatmentwith an acid halide or acid anhydride derived from a lower alkanoic acidor from an optionally alkyl-substituted pyrrole carboxylic acid, in thepresence of a tertiary base such as pyridine. Etherification with loweralkanols is effected, e.g. by treatment of the monoor polyhydroxycompounds embraced by the general Formula I with a reactive ester of therespective alkanol, especially with a hydrogen halide ester, thus, forexample, with a lower alkyl halide, in the presence of a base, such asan alkali hydride or alkali hydroxide.

The compounds of general Formula II to be used as starting materialscan, in turn, be obtained by a. partial alkaline hydrolysis of acompound of the general Formula Ill (III) with a compound of the generalFormula VI H N R VI) wherein:

R, represents a protected oxo radical, an esterified wherein 1 has the ng given for Formula and or etherified hydroxyl group and a hydrogenatom, optionally then acylating the hydroxyl groups in R or anetherified hydroxyl group and together with R and R, which have been setfree or reintroducing R an epoxy radical, or two hydrogen atoms, theacyl group -COR R and R each independently represent a protected d. thenreducing the reaction product of the general oxo radical, an esterifiedor etherified hydroxyl OTm a VII group and a hydrogen atom, or twohydrogen atoms, or, when occurring at a double bond, one hydrogen atom,R represents an aor B-oriented hydrogen atom, R represents an a-orientedhydrogen atom, an a-oriented hydroxyl group, or together with R, anepoxy radical, R represents an aor B-oriented hydrogen atom, or

an esterified or etherified hydroxyl group, and R and R eachindependently represent lower alkyl groups, hydrogen, or the phenylgroup, whereby double bonds may be present in the positions 5, 7, 9 (l1)and 16 corresponding to the dotted lines with the elimination of R Rand/or R in order to cleave off the acyl group -COR,,;

b. oxidizing the compound obtained of the general Formula IV (VII)wherein:

R R and R respectively, with the exception of the free oxo radical, Rrepresents the acyl group COR or hydrogen, and R,, R R and R have themeaning given for Formula I, by means of a complex hydride to a compoundof the general Formula VIII to convert the l8-hydroxy group into thel8-oxo radical;

c. reacting the oxidation product of the general Formula V (VIII) e.reacting the compound of the general Formula VIII with the equimolaramount or, when there are no secondary hydroxyl groups present, alsowith an excess of a reactive functional derivative of a halogeno-aceticacid in the presence of an acid-binding agent to obtain a compound ofgeneral Formula ll, and

f. optionally, before or after the halogeno-acetylation according to(e), setting free by mild acid hydrolysis, protected oxo radicals and/ora 3B-alkoxy group adjacent to a 3a,9a -epoxy radical.

The partial hydrolysis, step (a) of the above-defined reaction sequence,is preferably performed by reacting the compound of general Formula IIIwith about the equimolar or equivalent'amount of a basic substance in anorganic or organic/aqueous solvent at temperatures between about 20 and120C or the boiling temperature of the reaction medium. For example, thecompound of general Formula III is heated or boiled for a short periodwith about an equivalent amount of sodium, potassium or lithiumbicarbonate in alkanolic- /aqueous solution, e.g. in hydrous methanol orethanol; or a compound of general Formula III is reacted at roomtemperature or with heating with the equimolar amount of an alkali metalalkoxide, e.g. with sodium methoxide in a lower alkanol such asmethanol, ethanol or butanol. Weakly basic reagents such as theaforementioned alkali bicarbonates can also be used in excess when thetemperature and length of the reaction are so chosen that when thehydrolysis is interrupted, only the l8-hydroxyl group has been set free.Suitable as acyl groups -COR, and -COR are, e.g., acetyl, formyl,propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl or benzoylgroups. The two acyl groups may be identical or different, but in thelatter case -COR should be more readily split off than -CO-R e.g. anacetyl group or formyl group together with a pivaloyl or benzoyl groupas --COR The possibility of partially hydrolyzing the polyacyloxycompound of general Formula III in order to protect the -hydroxyl groupduring the subsequent oxidation of the l8-hydroxyl group which has beenset free, is an important prerequisite for the success of the entirereaction sequence leading from the compounds of general Formula III tothe compound of general Formula II and thus also for the production ofthe final products of general Formula I. That the compounds of generalFormula III could be partially hydrolyzed, was in no way predictable,for according to A. L. Nussbaum, F. E. Carlon, E. P. Oliveto, E.Townley, P. Kabasakalian and D. H. R. Barton, Tetrahedron 18 (1962),373-378, especially the upper part of page 375, the selective protectionof one or the other of the two hydroxyl groups in the positions 18 and20 in 18,2- 0B-dihydroxy-4-pregnen-3-one is not possible.

The oxidation according to step (b), in which the 18- hydroxy group isconverted into the 0x0 radical thus forming an aldehyde group, can beperformed e.g. by means of a 6-valent chromium compound, e.g. with aslight excess of a solution of chromium trioxide in hydrous sulphuricacid in acetone as reaction medium in the cold, furthermore also withchromium trioxide in pyridine. When ketal groups and/or a 3B-alkoxygroup together with a 3a, 9a-epoxy radical are present, special careshould be taken, when using chromium trioxide/sulphuric acid solutions,to maintain a low temperature, preferably at or below 0C.

The reaction of the compounds of geneal Formula V according to step (c)with a compound of general Formula VI such as methylamine, ethylamine,npropylamine, isopropylamine, n-butylamine, isobutylamine, benzylamineor ammonia, takes place e.g. at temperatures between about and C in aninert organic solvent such as benzene, toluene, methanol, ethanol orbutanol, and if necessary in a closed vessel, depending on the boilingpoint of the compound of general Formula VI and of the solvent as wellas on the reaction temperature. The compound of general Formula VI ispreferably used in excess and can optionally be used as sole reactionmedium. In the reaction according to the process, aminolysis of acyloxygroups which readily split off also occurs. The hydroxyl groups whichhave been set free are then optionally again acylated in the same manneras given for the hydroxyl groups of the end products, for example withan acetanhydridelpyridine mixture at room temperature. If desired, thehydroxyl group which has been set free can be left free, since it is notnecessarily affected in the following steps of the process.

The following reduction, step (d), of the imino compounds of generalFormula VII is e.g. performed with sodium boro-hydride in aqueousmethanol at temperatures between about 0 and 70C, preferably at roomtemperature.

For the introduction of the halogeno-acetyl'group into the secondary orprimary IS-amino group, step (e), for example, a halogeno-acetyl halideor halogenoacetanhydride, such as chloro-acetyl chloride, bromoacetylchloride, bromo-acetyl bromide, chloroacetanhydride,bromo-acetanhydride, in an inert organic solvent, e.g. a hydrocarbon orhalogenated hydrocarbon such as benzene or chloroform, is employed,whereby there is added as acid-binding agent, e.g., an aqueousalkali-metal hydroxide solution as second phase, as well as a solidinorganic basic substance such as potassium or sodium carbonate, or anorganic base such as N-ethyl-diisopropylamine, triethylamine, sym.collidine or pyridine. The reaction is preferably performed attemperatures between 0 and about 60C, whereby an excess ofhalogeno-acetylating agent should be avoided when there is a freesecondary hy-' droxyl group and/or a free BB-hydroxyl group as part ofacyclic hemiketal grouping together with the 3a,9a-- epoxy radicalpresent.

Conditions for the setting free of oxo radicals and/or cyclic hemiketalgroupings according to step (f) were already mentioned for thesubsequent modifications of the compounds of general Formula I.

Ketal groupings such as ethylene-dioxy groups can also be cleaved, e.g.,by heating with the appropriate starting materials in mixtures of asmall amount of hydrochloric acid with methanol and acetic acid to about50 to 70C.

Compounds of general Formula Ill can be produced from various knownstarting materials by reaction sequences which-with isolatedexceptions-are known. Two examples of such reaction sequences are givenbelow.

a) MeOH/HCI b) Ae o/Py A60 Ac!) 0 I AcO 0 Ac0a ACO W l Ac0 J 2, a) wasa) was f :7 I Q9 b M260 b z C"? J] /LiBr CH3O /L:l8r CHBO A pN0 PhCO0OHA120 2" ACO 0 M0 0 Ac!) Aao J 1K Ace- (q lL r s f/ A a) mm I n /Pd-Ba$0m/\.

W bu 2.,....c 4 f b 0H M IRY in BtOH CH3O IL @130 J C1130 l embraced byformula 111 According to the first reaction sequence, the startingcompound is 3B-acetoxy-20B-hydroxy a-pregnane (1), which can besubstituted as defined. Compounds of this type are described in theliterature. By oxidation with lead tetraacetate in the presence ofiodine in cyclohexane, and re-oxidation with CrO and subsequent reactionwith silver acetate followed by an aftertreatment with silica gel/water,is obtained 3B-acetoxy- 18,20-oxidoi-hydroxy-Sq-pregnane (2). Treatmentof (2) with acetic anhydride/pyridine, at elevated temperature, yields3,8,18}diacetoxy-20-oxo-Sd-pregnane (3), which can be converted bybromination with pyridimium hydrobromideperbromide and subsequentdehydrobromination with dimethyl formamide into 3B,18-diacetoxy-20-oxo-A' -5a-pregnene (4). A repeated bromination withN-bromo-succinimide and dehydrobromination with sodium iodide in acetoneyield 33,18-diacetoxy-20-oxo-A" -5a-pregnadiene (5). Epoxidation withp-nitroperbenzoic acid yields 3- 8,18-diacetoxy-14B,15B-epoxy-2O-oxo-A-5apregnene (6), which is converted by catalytic hydrogenation inethanol, in the presence of palladium on barium sulphate, into313,18-diacetoxy-14B-hydroxy-20- oxo-5a,17a-pregnane (7). Reduction withlithiumaluminiumtritert.butoxyhydride subsequently leads to3,8,18-diacetoxy-14B,2O -dihydroxy-Sa,17a-pregnane (8), which can beacetylated to 3,8,18,20 -triacetoxy- 14,B-hydroxy-5a,l7a-pregnane (9).The latter is embraced by the general Formula III.

In the second reaction sequence, the starting compound,(20R)-3-ethylenedioxy-20-hydroxy-A pregnadien-l8-acid lactone-( 20)(11), which is also known, is first reduced with lithium aluminiumhydride to the 18,20-dihydroxy compound. The subsequent cleaving of the3-ethylenedioxy group with a little hy- 65 chloroform/methanoldrochloric acid in acetic acid/methanol leads to (20R-)-3-oxo-18,2O-dihydroxy-A" -pregnadiene 12),-

which is hydrogenated with the calculated amount of hydrogen in thepresence of a palladium/charcoal catalyst to (20R )-3-oxol 8,20-dihydroxy-A -5B- pregnene (l3). Partial acetylation thereof withacetanhydride/pyridine at room temperature leads to (20R)-3-oxo-18-acetoxy-20-hydroxy-A -5B-pregnene (14),

acetylated with acetanhydride/pyridine to obtain 33-methoxy-3a,9a-epoxy-l 1a,] 8-diacetoxy-20-oxo-5B- pregnane (17). Onbromination with N-bromosuccinimide in 17-position and cleaving hydrogenbromide by means of lithium carbonate/lithium bromide,

3Bmethoxy-3a,9a-epoxy-l 101,1 8-diacetoxy-20-oxo- A -SB-pregnene (18) isobtained. Repetition of the two latter reactions yields3,B-methoxy-3a,9a-epoxy- 1 101,1 8-diacetoxy-2O -oxo-A -5/3-pregnadiene(19) Treatment thereof with p-nitro-perbenzoic acid in leads toBB-methoxy- 3a,9a:14B,15,B-diepoxy-l 1a,] 8-diacetoxy-20-oxo-ASB-pregnene (20), from which, by thorough hydrogenation in the presenceof palladium/barium sulphate catalyst in ethanol,3B-methoxy-3a,9a-epoxy-l1a,]8-diacetoxy-l4B-hydroxy-20-oxo-5B,l7a-pregnane (21) is obtained. This isfinally converted by reduction with sodium boro-hydride inmethanol/water and subsequent acetylation with acetanhydride/pyridineinto 35- methoxy-3a,9a-epoxy-l 101,1 8,20 -triacetoxy-l4,3-hydroxy-5B,l7a-pregnane (22), which is embraced by the general FormulaIII.

The above reaction sequences can also be performed analogously withcompounds which instead of the 3- acetoxy or 3-ethylene-dioxy group haveother protected hydroxyl groups or oxo radicals falling under thedefinition for R Analogous to the second reaction sequence, the startingmaterials having a protected functional group corresponding to thedefinition of R in 7-position can also be converted into compounds ofgeneral Formula III, whereby the functional group in 7-position can beleft or can be used to introduce a double bond into the 7,8-position. Itis, e.g., likewise possible to reintroduce a double bond into thel6,l7-position analogously to the conversion of the compound (17) intothe compound (18) in the second reaction sequence.

The invention relates also to those embodiments of the process for theconversion of compounds of general Formula II into those of generalFormula I as well as for the reaction sequence leading from thecompounds of general Formula III to the compounds of general Formula II,whereby the starting compound is one obtained at any particular stage asan intermediate product and the missing operations are carried out, orthe process is interrupted at some stage, or whereby a starting materialis formed under the reaction conditions, or whereby the reactioncomponents are optionally present in the form of their salts.

Belonging to the object of the invention are also the new startingmaterials for the present process corresponding to general Formula II,as well as the preliminary products of general Formula III and the otherintermediate products of general Formulas IV, V, VII and VIII.

Optionally, the new compounds of thegeneral Formula I obtained accordingto the invention and containing as R two hydrogen atoms, thusconstituting cyclic amines, are converted in the usual manner into theiracid addition salts with inorganic and organic acids. For example, to asolution of a corresponding compound of the general Formula I in anorganic solvent such as benzene, diethyl ether, methanol, ethanol oracetone, is added the acid desired as the salt component, or a solutionof the acid, and the salt, which has precipitated immediately or afterthe addition of a second organic liquid such as, e.g. diethyl ether tomethanol, is separated. Liberation of the bases from their acid additionsalts is likewise performed in the usual manner by reaction with basicsubstances such as, e.g. sodium carbonate or sodium bicarbonate.

For use as active substances for pharmaceutical preparations it ispossible to employ, instead of free basic compounds of the generalFormula I, pharmaceutically acceptable acid addition salts thereof, i.e.salts with such acids, the anions of which exhibit, in the case of thedosages in question, either no inherent pharmacological action or adesired one. Furthermore, it is of advantage if the salts to be used asactive substances crystallize well and are not, or only slightly,hygroscopic. For salt formation with compounds of the general For- LIImula I suitable for the purpose, it is possible to use, e.g.hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid,methanesulphionic acid, ethanesul phonic acid, B-hydroxyethanesulphonicacid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid,succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid,phenylacetic acid, mandelic acid, embonic acid orl,5-naphthalenedisulphonic acid.

The present invention also relates to the production of pharmaceuticalpreparations for application in human or veterinary medicine and whichcontain the new pharmacologically effective compounds of the generalFormula I of the present application as active substances, together witha pharmaceutical carrier. Used as carriers are organic or inorganicsubstances which are suitable for enteral administration, e.g. oral,parenteral, or topical administration. Suitable for the formationthereof are such substances which do not react with the new compounds,such as e.g. water, gelatine, lactose, starch, magnesium stearate,talcum, vegetable oils, benzyl alcohols, rubber, polyalkylene glycols,vaselines, cholesterol and other known medicament-carriers. Thepharmaceutical preparations can be in solid form, e.g. as tablets,dragees or capsules; or in liquid or semi-liquid form as solutions,suspensions, emulsions, ointments or creams. Optionally, thesepharmaceutical preparations are sterilized and/or they containauxiliaries such as preservatives, stabilizers, wetting or emulsifyingagents, salts for modifying the osmotic pressure, or buffers. They canalso contain other therapeutically valuable substances. The newsubstances can also serve as starting products for the production ofother valuable compounds.

The compounds of the general Formula I can also be used as animal-feedadditives.

The invention is described in more detail in the following examples;these in no way limit, however, the scope of the invention. Thetemperatures are given in degrees Centigrade. The rotations are measuredin chloroform; concentrations are given in parenthesis. The IR spectraare measured in chloroform, or in another solvent given in parenthesis;the absorption bands are given in cm. The, UV spectra are taken inethanol; absorption maxima are stated in nm, e-values are inparenthesis.

Celite is a tradename of the Johns-Manville International Corp., NewYork.

DETAILED DESCRIPTIONS EXAMPLE l 150 mg of 33,20i-diacetoxy-l4B-hydroxy-l8-(N- methyl-2-chloroacetamido)-5a,l7a-pregnane(see Example 7) are dissolved in 18 ml ofabsolute tetrahydrofuran and 18ml of absolute benzene; to the obtained solution are added, one afterthe other, mg of sodium hydride and 0.3 ml ofa solution of 160 mg ofethanol in ml of absolute tetrahydrofuran. The mixture is stirred for 3hours at 50; to the reaction mixture is then added ethyl acetate, andthe whole washed until neutral with saturated aqueous sodium chloridesolution. The crude product remaining behind after concentration byevaporation is chromatographed in ethyl acetate on silica gel. By thismeans are obtained mg of.l-methyl-2'-oxo-3B,20-diacetoxy-l413,18-(epoxyethanoimino)-50z,l7a-pregnane.After two crystallizations from acetone/hexane, the melting point is25l252. IR: I730, 1650, 1250. [a],,=100( 0.46).

EXAMPLE 2 105 mg of l-methyl-2'-oxo-3B,20-diacetoxy-148,18-(epoxyethanoimino)-a,17a-pregnane are boiled in 40 ml of absolutediethyl ether for 5 hours with 250 mg of lithium aluminium hydride. Thereaction mixture is then carefully decomposed with a little water,filtered off from the precipitated aluminium hydroxide, afterwardsrinsed with methylene chloride, and the filtrate concentrated byevaporation. Thus ob tained are 105 mg of crude l-methyl-3B,20-dihydroxy-l 4,8,18(epoxyethanoimino)-5a,17apregnane (IR: 3600). Theseare acetylated for ca. hours at room temperature in ml of aceticanhydride/pyridine mixture (1:1). By concentration of the reactionmixture in vacuo, and chromatography in ethyl acetate/methanol (9:1) ofthe crude product remaining behind are obtained 50 mg of l'-methyl-3,13,20f-diacetoxy-14/3,l8-(epoxyethanoimino)- 5a,17a-pregnane. M.P.after two crystallizations from methanol/water 198200 (decomposition).IR: 1730, 1250. [a],, 51 (0.37).

EXAMPLE 3 33 mg of 3Bmethoxy-3oz,9a-epoxy-l101,205-diacetoxy-l4B-hydroxy-18-(N-methyl-2- chloracetamido)-5B,l7a-pregnane(see Example 8) are dissolved in 3 ml of absolute tetrahydrofuran and 3ml of absolute benzene; first 20 mg of sodium hydride and then 0.1 ml ofa solution of 160 mg of ethanol in 100 ml of absolute tetrahydrofuranare added. The mixture is boileld for 4 hours under an argon atmosphere.The excess sodium hydride is then carefully decomposed by the additionof moist ether. Then the reaction mixture is diluted with ethyl acetateand washed neutral with saturated aqueous sodium chloride solution.After concentration by evaporation, the residual crude product ischromatographed in ethyl acetate on silica gel. 26 mg of1-methy1-2'-oxo-3fi-methoxy- 3a,9a-epoxy-1la,20-diacetoxy-1413,18-(epoxyethanoimino)-5B,l7a-pregnane is obtainedwhich, after recrystallizing once from acetone/hexane, melts at 239240.[04],) 64. (0.25). IR: 1725, 1650, 1250.

EXAMPLE 4 19 mg of l-methyl-2-oxo-3,8-methoxy3a,9a-epoxy-11a,20-diacetoxy- 1 4B, 18-(epoxyethanoimino)- 5,8,19ot-pregnane areboiled in a mixture of 7 ml of absolute ether and 2 ml of absolutetetrahydrofuran with 50 mg of lithium aluminium hydride for 5% hours.Then the excess lithium aluminium hydride is decomposed with saturatedaqueous ammonium sulphate solution, diluted with ethyl acetate andwashed neutral with aqueous sodium chloride solution. Afterconcentration byevaporation, the crude product which remains ischromatographed on silica gel in an ethyl acetate/methanol solution(10:1), the ethyl acetate portion of which having been previouslysaturated with 10% aqueous ammonia. 13 mg of crystalline l-methyl-3,B-methoxy-3a,9a-epoxy-1 la,20-dihydroxy-14B,l8-(epoxyethanoimino)-5/3,l7a-pregnane are obtained, which, after acrystallization from acetone/hexane, melts at 160180 with decomposition.IR: 3640, 3560, 3500-3300 broad, 1095, 1000, 950 in CH Cl EXAMPLE 5 10mg of l'-methyl-3B-methoxy-3a,9a-epoxy-11a,

-dihydroxy-143,18-(epoxyethanoimino)-5B,l 7apregnane are acetylated in 5ml of acetanhydridc/pyridine mixture (1:1 for 3 hours at The reactionmixture is then concentrated by evaporation in vacuum and the crudeproduct is chromatographed in ethyl acctate, which has been saturatedwith ammonia. on silica gel. 9 mg of 1-methyl-3B-methoxy-3a,9a-epoxy- 1la,20-diacetoxy-14,B,18-(epoxyethanoimino)- 5fi,17a-pregnane are thusobtained, which thus far it has not been possible to crystallize. IR:1725, 1250, 1100, 1005, 960.

EXAMPLE 6 30 mg of 1'-methyl-3,B-methoxy-3a,9a-epoxy- 11a,20-dihydroxy-14B,l8-(epoxyethanoimino)- 5,8,l7a-pregnane are allowedto stand for 24 hours at room temperature in a mixture of 1 ml of 70%aqueous perchloric acid and glacial acetic acid to make 10 m1. Then thereaction mixture is alkalized with 2 N sodium hydroxide solution, ethylacetate is added, the solution obtained is washed neutral with saturatedsodium chloride solution and concentrated by evaporation. About 23 mg ofcrude 1'-methyl-3a,9a-epoxy-3B,l 101,205-trihydroxy-143,18-(epoxyethanoimino)-5B,17apregnane remain which arechromatographed in a mixture of ethyl acetate, which has been saturatedwith 10% aqueous ammonia solution and then dried with magnesiumsulphate, and methanol 10:1 on very pure silica gel. About 15 mg of puresubstance are obtained. IR: 3620, 3560, 3500-3300 broad.

EXAMPLE 7 The 3fi,20-diacetoxy-l4B-hydroxy-18-(N-methyl-2-chloroacetamido)-5a,17B-pregnane used in Example 1 as starting materialcan be produced in the following manner:

a. g of lead tetracetatc are dried for Z'hours in darkness at roomtemperature. To this are then added 20 g of dry calcium carbonate, andthe mixture is refluxed for one hour, with stirring, in 1700 ml of abs.cy-

ture is thereby observed. After cooling, the mixture is filtered throughcotton wool, and the filtrate concentrated in vacuum. Theconcentration-residue is oxidized for 30 minutes in 800 ml of acetone,at a temperature of ca. 5, with an excess of an 8 N solution of chromiumtrioxide in 8 N sulphuric acid. 20 ml of isopropanol is then added, thewhole diluted with ethyl acetate, and washed until neutral withsaturated aqueous sodium chloride solution. The crude product obtainedafter drying and concentration by evaporation of the organic phase isrefluxed for 3 hours with stirring, in 1,500 ml of abs, methanol with 25g of silver acetate. The mixture is afterwards filtered through cottonwool, concentrated in vacuum, dissolved in ether, and filtered onneutral aluminum oxide (Act. 111). The thereby obtained crude product ischromatographed on 2 kg of silica gel, Merck (grain size 0.05-0.2 mm),which has been previously deactived with 200 ml of water. With abenzene/ethyl acetate mixture (10:1) are thereby eluted 7.5 g of3B-acetoxy-l8,20-epoxy-20- hydroxy-Sa-pregnane, M.P-. 169 (twicerecrystallized from acetone/hexane). [01],, 33 (0.45). IR: 3590, 1725,1250.

e. To 976. mg of 3,818-diacetoxy-20-oxo-A -apregnadiene in 40 ml ofchloroform there are added 488 mg of p-nitroperbenzoic acid, and themixture is stirred in darkness for 19 hours at room temperature.

b. l g of 3B-acetoxy-l 8,20-epoxy-20-hydroxy-5a- 5 The mixture is thendiluted with ethyl acetate, and sucpregnane is dissolved in a mixture of7 ml of pyridine and 7 ml of acetanhydride, and the solution obtained isheated in a nitrogen atmosphere for 10 hours to 95. The solution isallowed to cool; it is then diluted with ethyl acetate, and washedsuccessively with 2 N aqueous hydrochloric acid, saturated aqueoussodium chloride solution, saturated aqueous sodium bicarbonate solution,and again with saturated aqueous sodium chloride solution until theneutral point is attained. The solution is then dried with magnesiumsulphate, concentrated in vacuum, and chromatographed on the 100-foldamount of silica gel which has been deactivated previously again with 10percent water. With benzene/ethyl acetate mixture (10:1) are therebyfirstly eluted 395 mg of 35,18-diacetoxy-20-oxo-5apregnane; M.P. 107after two crystallizations from acetone/hexane, [a] 70 (0.46). IR: 1740,1710, 1240 (in CCl Subsequent fractions consisted of 386 mg ofunmodified 3B-acetoxy-18,20-epoxy-20- hydroxy-Sa-pregnane.

c. An amount of 1.04 g of 3B,18-diacetoxy-20-oxo- Sa-pregnane isbrominated in 50 ml of dichloromethane with 1.13 g of 90%pyridinehydrobromideperbromide for 30 minutes at room temperature whilststirring is maintained. The reaction mixture is then diluted with ethylacetate, repeatedly washed with saturated aqueous sodium chloridesolution, dried over magnesium sulphate, and evaporated in vacuum.Thereby obtained are 1.23 g of crude 3l3,l8-diacetoxy-l7f-bromo-20-oxo-Sa-pregnane which is advantageously dehydrobrominated, without anypurification, by 3 hours boiling in 20 ml of abs. dimethyl formamideunder nitrogen. After cooling, the product is diluted with ethyl acetateand washed at least 5 times with water. The organic phase is then driedwith magnesium sulphate, and evaporated in vacuum. The'obtained crudeproduct is first filtered in dichloromethane solution on neutralaluminium oxide (Act. lll), and afterwards chromatographed inbenzene/ethyl acetate solution (6:1) on silica gel. By this meaans'areobtained 860 mg of 35,18- diacetoxy-20-oxo-A -5oz-pregnene which, aftertwo crystallizations from acetone/hexane, melts at 135. [a] 44(0.35).1R:1725, 1670, 1590, 1250. UV: 238 (e 8920).

d. An amount of 800 mg of 3B,18-diacetoxy-20 oxo- 66 -5a-prenene isrefluxed for 1 hour, with stirring, with 650 mg of N-bromosuccinimide in50 ml of carbon tetrachloride in the presence of 50 mg ofazo-bisisobutyronitrile. The mixture is allowed to cool; it is thenfiltered off from the succinimide which has crystallized out,subsequently washed with carbon tetrachloride, and evaporated in vacuum.The crude bromination product is afterwards boiled for 3 hours with l gof sodium iodide in 100 ml of acetone, the whole concentrated in vacuoto ca. 25 ml, diluted with ethyl acetate, and successively washed withaqueous solutions of sodium thiosulphate and sodium chloride. Theorganic phase dried over magnesium sulphate is concentrated in vacuum,and the crude product chromatographed in benzene/ethyl acetate solution(6:1 on silica gel. Thus obtained are 512 mg of oily3B,l8-diacetoxy-20-oxo- A -Sa-pregnadiene. IR: 1735, 1650, 1530, 1240(CCl UV: 312 (e 6250).

cessively washed with aqueous solutions of potassium iodide, sodiumthiosulphate, sodium chloride, sodium bicarbonate, and again sodiumchloride, until the neutral point is attained. The ethyl acetate phasedried with magnesium sulphate is concentrated in vacuum in a rotaryevaporator, and the crude product chromatographed in benzene/ethylacetate solution (4:1) on silica gel. In this manner are obtained 550 mgof 35,18- diacetoxy-14BlSB-epoxy-ZO-oxo-A -5a-pregnene,

M.P. l28-l29(twice crystallized from acetone/hexane). q] =+6 2 O.42).IR: 1725, 1670, 1600, 1250.

UV: 249 (e -8270). 1

f. An amount of 300 mg of 3B,l8-diacetoxy-l4B,15B epoxy-20-oxo-A'-5a-pregnene is exhaustively hydrogenated in 80 ml of ethanol in thepresence of 100 mg of 5% palladium on barium sulphate at roomtemperature and under normal pressure. After completion of the hydrogenabsorption, the catalyst is separated by filtration, and the filtrate isevaporated in vacuum. The crude hydrogenation product is then filteredon neutral aluminum oxide (Act. 111). Thus obtained are 282 mg of oily 3[3,1 8-diacetoxyl 4B-hydroxy-20-oxo-5a,l 7ozpregnane. 1R: 3600-3200broad, 1735, 1240 (CC1 g. An amount of 282 mg of 3B,l8-diacetoxy-14B-hydroxy-20-oxo-5a,l7a-pregnane is stirred in ml of tetrahydrofuran with430 mg of lithium aluminium tritert. butoxy-hydride for 5 hoursat roomtemperature. The excess hydride is then decomposed with 5% aqueousacetic acid (ca. 2 ml), diluted with ethyl acetate and washedsuccessively with aqueous solutions of sodium bicarbonate and sodiumchloride until the neutral point is attained. The crude product obtainedafter drying and concentration in vacuum is chromatographed inbenzene/ethyl acetate solution (1:1) on silica gel,

droxy-5a ,l7a-pregnane are eluted. 1R; 3600-3300 broad, 1735, 1240 (CC1h. 150 mg of 33,18-diacetoxy-l4B,20-dihydroxy- 50z17a-pregnane areallowed to stand in 10 ml of pyridine/acetanhydride mixture (1:1) for 16hours at room temperature. The acetylation mixture is then concentratedin vacuum, whereby 115 mg of chromatographically homogeneous oily3,8,18,20 5- triacetoxy-l4B-hydroxy-5oi,l7a-pregnane are obtained. IR:3580, 1735, 1240((CC1.,).

i. An amount of mg of 33,1 8, 20-triacetoxy-l4,B-hydroxy-5a,l7a-pregnane is hydrolyzed in a mixture of 32 ml of methanoland 3.5 ml of aqueous 1% sodium bicarbonate solution for 5 minutes atboiling temperature. The solution is then neutralized with glacialacetic acid, diluted with ethyl acetate, and washed until neutral withaqueous sodium chloride solution. The crude product remaining behindafter concentration by evaporation is chromatographed in benzene/ethylacetate solution 1:1 on silica gel. Firstly eluted thereby are 38 mg ofunmodified starting material, there then follow 67 mg of transitionfractions, and aftewards 49 mg of 3B,20-diacetoxy-14B,l 8-dihydroxy-5a,l7a-pregnane, M.P. -18l (twice crystallized from acetonelhexane). [(11 7(0.46). IR: 36'00-3300, 1730, 1240 (CCl j. 95 mg of3B,20-diacetoxy-l4B,l8-dihydroxy- 501,1 7a-pregnane are oxidized in 10ml of acetone at 0 19 for 2 minutes, with stirring, with an excess of an8 N solution of chromium trioxide in 8 N sulphuric acid. The chromiumtrioxide excess is then decomposed by the addition of 2 ml ofisopropanol. The reaction mixture is taken up in ethyl acetate, andwashed with saturated aqueous sodium chloride solution until a neutral,co-

lourless organic phase results. After drying and concentration thereofin vacuum, 85 mg of crude product are obtained, which arechromatographed in benzene/ethyl acetate solution (1:1) on silica gel.Eluted thereby are 65 mg of 3,B,20tf-diacetoxy-14,8-hydroxy-l8-oxo-511,1 7a-pregnane which, after two crystallizations from acetone/hexane,melts at l70-171. [a],, (0.42). IR: 3610, 3480, 2720, 1735, 1720 1710(double bands for the aldehydecarbonyl), 1240 (CCl k. An amount of 270mg of 3a,20-diacetoxy-l4,8- hydroxy-l8-oxo-5a,l7a-pregnane is heatedwith 50 ml of methylamine in 50 ml of abs. benzene for 15 hours in abomb tube to 120. The mixture is concentrated in vacuo, dissolved in 10ml of acetanhydride/pyridine mixture (1:1), allowed to stand for 3 hoursat room temperature, and concentrated in vacuum, wherebythylimino)-5a,l71x-pregnane are obtained. IR: 3300 broad, 2760, 1730,1655, 1240 CC1 1. The methylimino compound obtained according to (k) isreduced in 50 ml of methanol with 300 mg of sodium borohydride in ofwater at for 20 minutes. To the reaction mixture is then added ethylacetate, the whole washed until neutral with saturated aqueous sodoiumchloride solution, and concentrated by evapob. 10.7 g of(2OR)-3-ethylenedioxy-l 8,20- dihydroxy-A "-pregnadiene are refluxed fortwo hours in 1,500 ml of acetone and 100 ml of water with 1.5 g ofp-toluenesulphonic acid. The reaction solution is then concentratedunder vacuum to about 500 ml. By careful addition of water to thissolution, the desired (2OR)-3-oxol 8,20-dihydroxy-A -pregnadieneprecipitates as crystals. These are then suction filtered, washedneutralwith a large amount of water, dried, and recrystallized once frommethanol/water to yield 7 g of crystals having a melting point of 194.[11],, +59 (0.61 ).1R: 3600, 3550-3100, 1660, 1615. UV: 244 (16700).

c. 7 g of (2OR)-3-oxo-l8,20-dihydroxy-A" pregnadiene are hydrogenated in250 ml of 0.1 N ethanolic potassium hydroxide solution in the presenceof I 1 g of 5% palladium/charcoal catalyst with one equivahydroxy-l8-(methylamino)-5o1,17o1-preganane are obtained. 1R: 3500-2600 broad,1730, 1250.

m. The methylamino compound obtained according EXAMPLE 8 The3B-methoxy-31x,91x-epoxy-l 11x,20-diacetoxy-14B-hydroxy-18-(N-methyl-2-chloracetamido)- 5B,17a-pregnane, used asstarting material in Example 3, can be produced as follows:

a. 10 g of (20R)-3-ethylenedioxy-20-hydroxy-A pregnadien-lS-acid lactone20) are boiled in 300 ml of absolute tetrahydrofuran with 7 g of lithiumaluminium hydride for 2 hours. Then the excess hydride is decomposedwith about 5 ml of saturated aqueous ammonium sulphate solution whilecooling with ice. Then 20 g of Celite are added and stirred for minutesat room temperature; the 'aluminium hydroxide/Celite mixture is removedby filtration, rinsed with ethyl acetate, and the filtrate isconcentrated by evaporation in vacuum to yield 9.7 g of (2OR)-3-ethylenedioxy-l 8 ,20-dihydroxy-A "-pregnadiene which, after acrystallization from methylene chloride/-- hexane, melts at 201. [11],,(0.49). IR: 3600, 3500-3200.

lent of hydrogen. After the calculated amount of hydrogen has been takenup, the hydrogenation is interrupted, and the catalyst is removed fromthe solvent by filtration. By the careful addition of water to thefiltrate, (2OR)-3-oxo-18,20-dihydroxy-A -5B- pregnene precipitates ascrystals. After suction filtration, washing neutral with a large amountof water, drying in vacuum and recrystallization from methanol/water,6.7 g of pure crystallization product having a melting point of 198 areobtained. [11],, 2 (0.49). IR: 3600, 3500-3200, 1705.

d. 5.1 g of (2OR)-3-oxo-18,20-dihydroxy-A -5B- pregnene in 60 m1 ofpyridine and 40 ml of acetanhydride are allowed to stand for 1 hour atroom temperature. Then the excess acetanhydride is decomposed by thecareful addition of 80 m1 of methanol, the temperature being kept atabout 0 by the addition of solid carbon dioxide in portions. Then thereaction mixture is left to stand for 30 minutes at room temperature,evaporated in vacuum, and the crude portion is chromatographed inbenzene/ethyl acetate (1:1) on silica gel. First 1.5 g of(2OR)-3-oxo-l8,20-diacetoxy-A"-5B- pregnene [1R1 1740-1700, 1250], whichcan be reconverted into the starting material for the acetylation byalkaline hydrolysis in 5% methanolic potassium hydroxide solution. Laterfractions yield 2.1 g of (20R)- 3-oxo-l 8-acetoxy-20-hydroxy-A-SB-pregnene which, after crystallization from methylene chloride/-hexane, melts at 1 10. [a],,=0 (0.48). IR: 3580, 1730, 1710, 1250.Further fractions yield 2.0 g of unmodified(2OR)-3-oxo-l8,20-dihydroxy-A BB-pregnene.

e. 1.5 g of (2OR)-3-oxo-l8-acetoxy-20 -hydroxy- 5 -5 ,B-pregnene in 100ml of acetone are oxidized at room temperature while stirring with anexcess of an 8 N solution of chromium trioxide in 8 N sulphuric acid for15 minutes. Then 5 ml of methanol are added, the mixture is diluted withethyl acetate, and the organic phase is washed with saturated aqueoussodium chloride solution. After drying and concentration by evaporation,1.49 g of crude product are obtained which, dis- -solved indichloromethane, is filtered through neutral aluminium oxide (Act. 111).It is then crystallized from acetone/hexane to yield 1.4 g of3,20-dioxo-l8- acetoxy-A "-SB-pregnene, M.P. ll2l 14. [01],;+67(0.48).1R: 1745, 1720, 1710, 1230 (CCl f. 1.2 g of osmium tetroxideare added to 1.15 g of 3,- 20-dioxo-18-acetoxy-A -5B-pregnene in 15 mlof pyridine and allowed to stand for 6% days in the dark at roomtemperature. Then the reaction mixture is .evaporated to dryness invacuum with the repeated addition of benzene; the residue is dissolvedin 40 ml of freshly distilled dioxane. Then 1 40 ml of saturated,aqueous ammonium chloride solution are added and hydrogen sulphide ispassed through the two-phase system during one hour. 6 g of shreddedfilter paper are added. After heating for 1 hour at 70, the mixture isfiltered through Celite and then successively washed with 500 ml ofethyl acetate, 100 ml of methanol, 100 ml of water, 100 ml ofdichlorornethane and again 500 ml of ethyl acetate. The filtrate isdiluted with more ethyl acetate and washed several times with saturated,aqueous ammonium chloride solution. Then the organic phase is dried withmagnesium sulphate and concentrated by evaporation in vacuum. 1.23 g ofcrude product are obtained which, in ethyl acetate/methanol solution(9:1 is chromatographed on silica gel to yield 1.13 g of 38,11a-dihydroxy-3a,9a-epoxy-18acetoxy- 20 -oxo-B-pregnane [IR:3600-3200, 1740, 1710, 1230 (CCl which is further processed withoutpurification.

g. 775 mg of 313,1 1a-dihydroxy-3a,9a-epoxy-18-acetoxy-20-oxo-5,B-pregnane in 30 ml of 0.1 N absolute methanolichydrogen chloride solution are left for 20 minutes at room temperature.Then the mixture is poured onto a saturated, aqueous sodium bicarbonatesolution, extracted with ethyl acetate, and the resulting organic phaseis washed several times with saturated, aqueous sodium chloridesolution. After drying the solution with magnesium sulphate andconcentration by evaporation, the crude product obtained (745 mg) isacetylated in ml of acetanhydride/pyridine mixture 1:1) for 3% hours at70. The reaction mixture is then concentrated by evaporation in vacuum,and the crude product obtained is filtered in dichloromethane on neutralaluminium oxide (Act. 111) to yield 805 mg of 3/3methoxy-301,901-epoxy-l 101,18-diacetoxy-20oxo-5B- pregnane which, afterone crystallization from acetone/hexane, melts at 151152. [01],, +l06(0.46). IR: 1735, 1705, 1245.

h. 500 mg of 3B-methoxy-301,901-epoxy-1101,18- diacetoxyZO-oxo-SB-pregnane in ml of carbon tetrachloride are boiled for 1 hourwith 208 mg of finely pulverized 96% N-bromosuccinimide and 10 mg ofazabis-isobutyronitrile while irradiating externally with a 1,000 Wincandescent lamp. After cooling, the precipitated succinimide isremoved by filti 'ation, rinsed with carbon tetrachloride, and thefiltrate is concentrated by evaporation in vacuum. The resultantbromination product, without purification, is heated at 120 for 160minutes under a nitrogen atmosphere in 40 ml of absolute dimethylformamide with 500 mg of lithium carbonate and 500 mg of lithiumbromide. The mixture is then diluted with a large amount of ethylacetate, and the organic phase is washed at least 5 times with water.After drying and evaporating the ethyl acetate phase, 488 mg of crystalsare obtained which, in dichloromethane, are filtered on neutralaluminium oxide (Act. 111) to yield 435 mg of 3B-methoxy-3a,901-epoxyl101,18-diacetoxy-20-oxo-A-SB-pregnene which, after crystallizing twice(307 mg), melts at 167"-168. [01],, =+61(0.53).1R: 1730, 1668, 1590,1245. UV: 237 (8750). After chromatography of the mother liquor inhexane/acetone solution (3:1) on silica gel and subsequentcrystallization from acetone/hexane, 37 mg more of the product can beobtained.

i. 500 mg of 3B-methoxy-301,901-epoxy-1101,18- diacetoxy-20-oxo-A-5B-pregnene in 150 ml of carbon tetrachloride are boiled for 17 minuteswith 240 mg of 96% N-bromosuccinimide and 20 mg ofaza-bisisobutyronitrile while irradiating externally with a 1,000 Wincandescent lamp. After cooling, the precipitated succinimide isremoved by filtration. After concentration of the filtrate byevaporation, the residue obtained is dissolved in 50 ml of absolutedimethyl formamide and heated under nitrogen for 10 minutes at 130 whilestirring with 500 mg of lithium bromide and 500 mg of lithium carbonate.The mixture is then substantially concentrated in vacuum, diluted withethyl acetate, and washed several times with water. After drying andconcentration by evaporation of the organic phase, the crude productobtained is chromatographed in benzene/ethyl acetate solution (2:1) onsi1 ica gel to yield 330 mg of 3/3-methoxy-301, 901-epoxy- 1101,18-diacetoxy-20-oxo-A' -5,B-pregnadiene which, after crystallizingonce from acetone/hexane, melts at 146l47. [01] =+302(0.5O). IR: 1730,1645, 1525 1465,1245, 845. UV: 312 (10550).

j. 250 mg of 3B-methoxy-3a,9a-epoxy-l 101,18- diacetoxy-20-oxo-A-5B-pregnadiene which has been purified by chromatography but notrecrystallized, are boiled for minutes with 500 mg of p-nitroperbenzoicacid in a mixture of ml of chloroform and 1 ml of absolute methanol. Themixture is then diluted with ethyl acetate, and successively washed withice-cold, aqueous solutions of sodium iodide, sodium thiosulphate,sodium chloride, sodium bicarbonate and again sodium chloride. Afterconcentration of the organic phase by evaporation, the crude productobtained is chromatographed in hexane/acetone solution (2:1) on silicagel to yield 210 mg of 3B-methoxy- 301,901: 143,1 SB-diepoxy-l101,18-diacetoxy-20-oxo-A SB-pregnene which, after crystallizing 3 timesfrom acetone/hexane,melts at 198. [ct],,=+66 (0.58). IR: 1735, 1670,1605, 1240. UV: 248 (6890).

k. 100 mg of 3B-methoxy-3o1,901:14B,15B-diepoxy- :,1S-diacetoxy-2O-oxo-A-SB-pregnene in 20 ml of ethanol are thoroughly hydrogenated in thepresence of 40 mg of 5% palladium on barium sulphate. Then the catalystis removed by filtration. Chromatography in benzene/ethyl acetatesolution (1:1) on silica gel yields 55 mg of3B-methoxy-3a,9a-epoxy-11a,18-diacetoxy- 14B-hydroxy-20-oxo-5B,l701pregnane which, after crystallizing once from acetone/hexane, melts at154. [ab 0 (0.40). IR: 3600, 3400 broad, 1735, 1705, 1245.

l. 200 mg of sodium boro-hydride in 1 ml of water are added at roomtemperature to 197 mg of 3B-methoxy- 3a,901-epoxy-l101,18-diacetoxy-l4B-hydroxy-20-oxo- 5B,1701-pregnane in 10 ml ofmethanol. The mixture is then stirred for 20 minutes at roomtemperature, diluted with a large amount of ethyl acetate, and theresulting organic phase is washed neutral with saturated, aqueous sodiumchloride solution. It is then dried with magnesium sulphate andevaporated in vacuum. The resultant crude product is acetylated in 20 mlof pyridine/acetanhydride mixture (1:1) for 3 hours at room temperature,then evaporated in vacuum and chromatographed in benzene/ethyl acetatesolution (1:1) on silica gel, whereby 172. mg of 3fl-methoxy-3a,901-epoxy-1 101,18,20f'triacetoxy-l4B-hydroxy- 5B,1701-pregnane areeluted. After crystallizing twice from acetone/hexane, it melts at [01]+7 (0.31). IR: 3570, 1725, 1250.

m. 132 mg of 3B-methoxy-301,901-epoxy-1 101,18,20-triacetoxy-l4B-hydroxy-5B,l701-pregnane are boiled for 7 minutes in 18ml of a 0.1% sodium bicarbonate solution in 90% aqueous methanol. Thereaction solution is then poured onto ice, immediately extracted withethyl acetate, and the organic phase is washed neutral with saturated,aqueous sodium chloride solution. After drying and concentrating byevaporation of the ethyl acetate phase, the crude product obtained ischromatographed in benzene/ethyl acetate solution (1:1) on silica gel toyield, besides 18 mg of starting material, 83 mg of3,B-methoxy-3a,9a-epoxy-l104,20-diacetoxy-14B,18-dihydroxy-5B,17a-pregnane which, after crystallizingonce from acetone/hexane, melts at 203-205. [11],, 2 (0.47). IR: 3600,3460 broad, 1725, 1250.

n. 90 mg of 3B-methoxy-3a,9a-epoxy-l101,205-diacetoxy-l4/3,18-dihydroxy-5,8,17a-pregnane in 10 ml of acetone areoxidized at with stirring for 3 minutes with a slight excess of an 8 Nsolution of chromium trioxide in 8 N aqueous sulphuric acid (0.35 ml).Then the excess chromium trioxide is decomposed by the addition ofisopropanol, the mixture is diluted with ethyl acetate, and washedneutral as quickly as possible with saturated, aqueous sodium chloridesolution. After drying and concentration by evaporation of the ethylacetate phase, the resulting crude product is chromatographed inbenzene/ethyl acetate solution (1:1) on silica gel to yield 62 mg of3/3-methoxy-3a,9a-epoxy- 1la,20-diacetoxy-l4B-hydroxy-l8-oxo-5B,17apregnane which, aftercrystallizing once from acetone/- hexane, melts at 209. [01],, +13(0.40). IR: 3580, 3450, 2730, 1730, 1705, 1250.

o. 64 mg of 3B-methoxy-3a,9a-epoxy-l 101,205- diacetoxyl 4B-hydroxy-l8-oxo-5B,l 7a-pregnane are heated with 1 ml of methylamine in ml ofabsolute benzene for 15 hours in a closed tube at 120. After evaporatingin vacuum, the residue is dissolved in 10 ml of acetanhydride/pyridinemixture (1:1), then left for 3 hours at room temperature andconcentrated by evaporation in vacuum. 67 mg of 3/3-methoxy-3a,9aepoxy-l1a,20-diacetoxy-14B-hydroxy-18- methylimino-5,B,17a-pregnane areobtained. IR: 3200 broad, 1725, 1665, 1250.

pjThe methylimino compound obtained according to (o) is reduced in 10 mlof methanol with 75 mg of added at 0. After 10 minutes, the solution isdiluted What is claimed is: 1. A compound of the Formula I wherein Rrepresents a lower alkyl group, the benzyl group or hydrogen,

R represents an oxo radical or two hydrogen atoms,

R represents oxo or a ketal derived from a lower alkanediol or loweralkanols, or hydroxyl, hydroxyl esterified with a lower alkanoic acid orhydroxyl etherified with a lower alkanol or benzyl alcohol and ahydrogen atom,

R represents oxo or a ketal derived from a lower alkanediol or loweralkanols, or hydroxyl, hydroxyl esterified with a lower alkanoic acid orhydroxyl etherified with a lower alkanol or benzyl alcohol and ahydrogen atom, or hydroxyl, hydroxyl etherifled with a lower alkanol orbenzyl alcohol and together with R, an epoxy radical,

R and R each independently represent oxo or a ketal derived from a loweralkanediol or lower alkanols, or hydroxyl, hydroxyl esterified with alower alkanoic acid or hydroxyl etherified with a lower alkanol orbenzyl alcohol and a hydrogen atom, or two hydrogen atoms, or, whenoccurring at a double bond, one hydrogen atom,

R represents an aor B-oriented hydrogen atom,

R represents an a-oriented hydrogen atom, an a-oriented hydroxyl group,or together with R, an epoxy radical, and

R represents an aor ,B-oriented hydrogen atom, or hydroxyl, hydroxylesterified with a lower alkanoic acid or hydroxyl etherified with alower alkanol or benzyl alcohol,

whereby double bonds may be present in the positions 5 or 4, when R,represents a free oxo radical, as well as 7, 9 (11) ,and 16corresponding to the dotted lines with the elimination of R R and/or R9,

as well as pharmaceutically acceptable acid addition salts ofa compoundof Formula I in which R designates two hydrogen atoms with the exceptionof Batrachotoxinin A.

2. A compound according to claim 1, having Formula 11. A compoundaccording to claim 2 which is lmethyl-3a,9a-epoxy-3,B,lla,20--trihydroxyl 4,8,] 8- (epoxyethanoimino)-B,l7a-pregnane. 12. Acompound of the Formula ll wherein:

R represents a lower alkyl group or the benzyl group, whereby doublebonds may be present in the positions 5, 7 and 16 corresponding to thedotted lines, (11) with the elimination of R and R accordingly, as wellas pharmaceutically acceptable acid addition salts ofa compound ofFormula la in which R repwherein: resents two hydrogen atoms. Xrepresents chloroe, bromo or lOdO, 3. A compound according to cl i 2, hi R represents a lower alkyl group, the benzyl group R represents the0x0 radical, or hydrogen R represents a h d l group or Iower alkanoyloxyR represents 0x0 or a ketal derived from a lower algroup together with ahydrogen atom, kaned ol or lower alkanols, or hydr oxyl, hydroxyl Rrepresents a lowgr |k l group or the benzy| esterrfled with a loweralkanoic acid or hydroxyl group, etherified with a lower alkanol orbenzyl alcohol R and R each represent two hydrogen atoms, or a and ahydrogen atomi h l group or lower alkanoyloxy group R represents oxo ora ketal derived from a lower algether with a hydrogen atom. kanediol orlower alkanols, or hydroxyl hydroxyl 4 A compound according to Claim 2,wherein esterified with a lower alkanoic acid or hydroxyl R representstwo hydrogen atoms, etherified with a lower alkanol or benzyl alcoholand together with R an epoxy radical,

R and R each independently represent oxo or a ketal derived from a loweralkanediol or lower alkanols, or hydroxyl, hydroxyl esterified with alower alkanoic acid or hydroxyl etherified with a lower alkanol orbenzyl alcohol and a hydrogen R represents a hydroxyl group or loweralkanoyloxy group together with a hydrogen atom,

R represents a lower alkyl group or the benzyl group,

R and R each represent two hydrogen atoms, or a hydroxyl group or loweralkanoyloxy group together with a hydrogen atom.

5. A compound according to claim 2 which is l'- 5methyl-2-oxo-3,8,20-diacetoxy-148,18-(epoxyethanoimino)-5a,l7a-pregnane.

6. A compound according to claim 2 which islmethyl-2-oxo-3B-methoxy-3a,9a-epoxy-l lct,20-diacetoxy-l4B,l8-(epoxycthanoimino)-5B,l70tpregnane.

7. A compound according to claim 2 which islmethyl-3B,20-dihydroxy-148,1S-(epoxyethanoimino)5a,l7a-pregnane.

8. A compound according to claim 2 which is lmethyl-3B,20-diacetoxy-l4B, 1 8-(epoxyethanoimino)-5a,l7a-pregnane.

9. A compound according to claim 2 which islmethyl-3B-methoxy.3a,9a-epoxy.l loz,20-dihydroxy-14,8,18-(epoxyethanoimino)-5B,l7a-pregnane.

10. A compound according to claim 2 which islmethyl-3/3-methoxy-3a,9oz-epoxy-l la,20-'diacetoxy-146,18-(epoxyethanoimino)-5B,l7a-pregnane.

at a double bond, one hydrogen atom, R represents an aor B-orientedhydrogen atom, R represents an a-oriented hydrogen atom, an aorientedhydroxyl group, or together with R, an epoxy radical, and R representsan aor B-oriented hydrogen atom, or hydroxyl, hydroxyl esterified with alower alkanoic acid or hydroxyl etherified with a lower alkanol orbenzyl alcohol, whereby double bonds may be present in the positions 5or 4, when R represents a free oxo radical, as well as 7, 9 (l l) and 16corresponding to the dotted lines with the elimination of R R andl/or R13. A compound according to claim 12 which is 35,- ZO-diacetoxyl4B-hydroxyl 8-( N-ImethyI-Z- .chloroacetamido)-5 01,1 7a-pregnane.

14. A compound according to claim 12 which is 313- methoxy-3a,9a-epoxy-lla,20-diacetoxy- 14B-hydroxyl8-(N-methyl-2-chloroacetamido)-5B,l7a-pregnane.

atom, or two hydrogen atoms, or, when occurring UNITED STATES PATENT ANDTRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,8693452 DATEDMarch i, 1975 INVENTOR(S) Hansuli Wehrli et 8.1

It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

Column 26, line 59, delete "20-diacetoxy" and insert 20 E -diacetoxyColumn 26, line 62, delete "20-diacetoxy" and insert 20 -diacetoxySigned and Scaled this Twenty-ninth Day Of March 1977 [SEAL] Arrest:

RUTH C. MASON C. MARSHALL DANN Allesting Officer Commissioner nflaremsand Trademarks

1. A COMPOUND OF THE FORMULA I
 2. A compound according to claim 1,having Formula Ia
 3. A compound according to claim 2, wherein R2represents the oxo radical, R3 represents a hydroxyl group or loweralkanoyloxy group together with a hydrogen atom, R4'' represents a loweralkyl group or the benzyl group, R5 and R6 each represent two hydrogenatoms, or a hydroxyl group or lower alkanoyloxy group together with ahydrogen atom.
 4. A compound according to claim 2, wherein R2 representstwo hydrogen atoms, R3 represents a hydroxyl group or lower alkanoyloxygroup together with a hydrogen atom, R4'' represents a lower alkyl groupor the benzyl group, R5 and R6 each represent two hydrogen atoms, or ahydroxyl group or lower alkanoyloxy group together with a hydrogen atom.5. A compound according to claim 2 which is 1''-methyl-2''-oxo-3 Beta,20 xi -diacetoxy-14 Beta ,18-(epoxyethanoimino)-5 Alpha , 17 Alpha-pregnane.
 6. A compound according to claim 2 which is1''-methyl-2''-oxo-3 Beta -methoxy-3 Alpha ,9 Alpha -epoxy-11 Alpha ,20xi -diacetoxy-14 Beta ,18-(epoxyethanoimino)-5 Beta ,17 Alpha -pregnane.7. A compound according to claim 2 which is 1''-methyl-3 Beta , 20 xi-dihydroxy-14 Beta ,18-(epoxyethanoimino)-5 Alpha ,17 Alpha -pregnane.8. A compound according to claim 2 which is 1''-methyl-3 Beta , 20 xi-diacetoxy-14 Beta ,18-(epoxyethanoimino)-5 Alpha ,17 Alpha -pregnane.9. A compound according to claim 2 which is 1''-methyl-3 Beta -methoxy.3Alpha ,9 Alpha -epoxy.11 Alpha ,20 xi -dihydroxy-14 Beta,18-(epoxyethanoimino)-5 Beta ,17 Alpha -pregnane.
 10. A compoundaccording to claim 2 which is 1''-methyl-3 Beta -methoxy-3 Alpha ,9Alpha -epoxy-11 Alpha ,20 xi -diacetoxy-14 Beta ,18-(epoxyethanoimino)-5Beta ,17 Alpha -pregnane.
 11. A compound according to claim 2 which is1''-methyl-3 Alpha , 9 Alpha -epoxy-3 Beta ,11 Alpha ,20 xi-trihydroxy-14 Beta ,18-(epoxyethanoimino)-5 Beta ,17 Alpha -pregnane.12. A compound of the Formula II
 13. A compound according to claim 12which is 3 Beta ,20-diacetoxy-14 Beta-hydroxy-18-(N-methyl-2-chloroacetamido)-5 Alpha ,17 Alpha -pregnane.14. A compound according to claim 12 which is 3 Beta -methoxy-3 Alpha ,9Alpha -epoxy-11 Alpha ,20-diacetoxy-14 Beta-hydroxy-18-(N-methyl-2-chloroacetamido)-5 Beta ,17 Alpha -pregnane.